Abstract
We aimed to clarify the mechanisms of male predominance of hepatitis B virus (HBV) -related hepatocellular carcinoma (HCC). Androgen receptor (AR) facilitates HCC cell growth, which was augmented by androgen (dihydrotestosterone [DHT]) and attenuated by anti-androgen (flutamide). AR upregulated the expressions of BIRC7, IGFBP3, and NTSR1 via increasing their promoter activities, which were enhanced by DHT. Wild-type HBV X (WT-HBx) upregulated AR transcription, which depended on DHT; whereas the effect of C-terminal carboxy-truncated HBx on AR transcription was independent of DHT. BIRC7, IGFBP3, and NTSR1 increased the growth of HCC. High expression of BIRC7 and NTSR1 contributes to poor HCC outcomes in male patients, but not in female patients. Downregulation of NTSR1 inhibits tumor growth in male mice rather than in female mice. Conclusively, AR promotes HCC at least partially via upregulating BIRC7, IGFBP3, and NTSR1, which is enhanced by androgen and HBx. BIRC7 and NTSR1 facilitate HCC progression in a male-predominant manner.